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FSH/FSHR/TGF-β1/SMADS SIGNALING CASCADE MEDIATES OVARIAN FIBROSIS RESULTING IN OVARIAN AGING

卵巢 促卵泡激素受体 内分泌学 促卵泡激素 卵泡发生 内科学 卵泡 卵巢储备 免疫印迹 生物 纤维化 天狼星红 男科 颗粒细胞 促性腺激素 激素 医学 促黄体激素 细胞生物学 不育 胚胎 低温保存 怀孕 遗传学 生物化学 基因
作者
Yanye Zhang,Dan Zhang
出处
期刊:Fertility and Sterility [Elsevier]
卷期号:120 (4): e33-e33
标识
DOI:10.1016/j.fertnstert.2023.08.129
摘要

Whether progressively elevated FSH during physiological ovarian decay could be involved in ovarian aging via regulating ovarian fibrosis. We first established a mouse model of high serum FSH levels without dramatic decrease in estrogen via GnRHa and FSH injections instead of oophorectomy. Further, we blocked FSH action in mice with high FSH by anti-FSHβ antibodies (FSHAb) treatment. The mice serum levels of FSH, E2, and follicle numbers were measured in each group. Ovarian fibrosis was assessed by Masson trichrome and Sirius red staining, transmission electron microscopy, and expressions of several fibrotic molecules. Primary mouse ovarian fibroblasts (MOFs) were isolated and purified from the ovaries of 3-week-old mice and the FSHR expression was confirmed by Western blot. Fshr was knocked down in MOFs by siRNA. RNA-seq was used to analyze the transcriptomes of mouse ovaries from those treated with FSHAb or IgG. And the CUT&Tag assay was conducted on the FSH-treated MOFs. Differences among each group were compared using a two-tailed unpaired t-test for two groups and a one-way analysis of variance for multiple groups. p < 0.05 was considered statistically significant. We found that high FSH induced a significant decline in ovarian follicle numbers, especially the primordial and primary follicles, regardless of whether E2 was lower or normal. We also observed accelerated ovarian fibrosis in mice with higher FSH. Anti-FSHβ antibodies treatment could significantly reduce ovarian fibrosis in mice with high FSH and increase the primordial and primary follicles numbers. The functional FSHR is expressed in MOFs. FSH could significantly induce the expression of fibrotic molecules (COL3A1, COL5A2, COL1A1, and COL1A2) in MOFs in a dose and time-dependent manner, which could be reversed by Fshr knockdown. Mechanistically, GO and KEGG analysis indicated downregulation of TGFβ signaling in the ovaries of mice treated with FSHAb, compared with those treated with IgG. In vitro, FSH treatment could activate TGFβ1 signaling, as shown by increased phosphorylation of Smad2/3 and Smad4, and increased nucleus translocation of the Smads complex in MOFs. Fshr knockdown or SB431542, a TGF-β receptor 1 inhibitor, could suppress FSH-induced Smads complex activation. Further, the CUT&Tag assay showed that FSH significantly increased the direct binding of p-Smad3 to the genomic regions of Col1a1, Col1a2, Col3a1, and Col5a2. We proved that high serum FSH levels promoted ovarian fibrosis through FSHR/TGF-β1/Smads signaling pathway, leading to decreased ovarian reserve. Blocking FSH, silencing Fshr, or inhibiting the TGF-β1 pathway could effectively reduce ovarian fibrosis and restore the number of follicles.

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